The impact of primary percutaneous coronary intervention strategies during ST-elevation myocardial infarction on the prevalence of coronary microvascular dysfunction

Coronary microvascular dysfunction (CMD) is a common complication of ST-segment elevation myocardial infarction (STEMI) and can lead to adverse cardiovascular events. This is a non-randomized, observational, prospective study of STEMI patients with multivessel disease who underwent primary PCI, grouped based on whether they underwent balloon pre-dilatation stenting or direct stenting of the culprit lesion. Coronary physiology measurements were performed 3 months post-PCI including coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) measurements at the culprit vessel. The primary endpoint was the prevalence of CMD at 3 months, defined as IMR ≥ 25 or CFR < 2.0 with a normal fractional flow reserve. Secondary endpoints included major adverse cardiovascular events (MACE) at 12 months. Two hundred ten patients were enrolled; most were men, 125 (59.5%), with a median age of 65 years. One hundred twelve (53.2%) underwent balloon pre-dilatation before stenting, and 98 (46.7%) underwent direct stenting. The prevalence of CMD at 3 months was lower in the direct stenting group than in the balloon pre-dilatation stenting group (12.24% vs. 40.18%; p < 0.001). Aspiration thrombectomy and administration of intracoronary glycoprotein IIb/IIIa inhibitors were associated with lower odds of CMD (OR = 0.175, p = 0.001 and OR = 0.113, p = 0.001, respectively). Notably, MACE in patients who underwent direct stenting was lower than in those who underwent balloon pre-dilatation before stenting (14.29% vs. 26.79%; p = 0.040). In STEMI patients with multivessel disease, direct stenting of the culprit lesion, aspiration thrombectomy and administration of intracoronary glycoprotein IIb/IIIa inhibitors were associated with a lower prevalence of CMD at 3 months and lower incidence of MACE at 12 months compared with balloon pre-dilatation stenting. This trial is registered at https://ichgcp.net/clinical-trials-registry/NCT05406297.


Study inclusion and exclusion criteria
Participants were adults aged 40 years and older with STEMI (ST elevation ≥ 2 mm in ≥ 2 contiguous chest leads or ≥ 1 mm in ≥ 2 contiguous limb leads) who had received dual antiplatelet therapy (acetylsalicylic acid 300 mg and ticagrelor 180 mg or clopidogrel 600 mg) at least 30 min prior to primary PCI of the culprit vessel and subsequently underwent staged PCI of the non-culprit vessel 3 months later.
To exclude the potential influence of pre-existing microvascular obstruction, patients with a history of acute coronary syndrome were excluded.Patients who did not have a non-culprit coronary lesion and thus did not require a follow-up angiogram were also excluded.Patients with a serious comorbid illness such as sepsis, autoimmune disease, end-stage liver disease, end-stage renal failure, or solid organ cancer were excluded.Patients with severe valvular heart disease were excluded for significantly variable coronary physiology, and those with coronary artery bypass grafts were excluded because of altered coronary circulation 13 .Patients who underwent primary fibrinolysis, were allergic to contrast media, or were unable to tolerate adenosine triphosphate were also excluded.

Primary percutaneous coronary intervention
Primary PCI was performed using 6-Fr guiding catheters via radial or femoral arterial approaches.Patients were anticoagulated with a heparin bolus (70-100 U/kg) administered either intravenously, or directly into the coronary artery via the guiding catheter.The route of heparin administration was up to the discretion of the operator and was recorded prospectively.Two interventional cardiologists blinded to treatment allocation and study data independently assessed angiographic variables such as the TIMI flow score at baseline and at the completion of the primary PCI procedure.The treating operator independently determined whether to pursue balloon pre-dilatation stenting (balloon pre-dilatation followed by stenting) or direct stenting (stenting without balloon pre-dilatation).In accordance with standard procedural practices, all patients in both groups underwent post-dilation following stent implantation.This routine step ensures optimal stent apposition and expansion, minimizing the risks associated with potential stent under-expansion or malapposition.Iopromide (Ultravist, Bayer HealthCare Pharmaceuticals, Leverkusen, Germany) was used as the contrast agent.The study team documented information such as stent diameter and length, maximum inflation pressure, and the amount of contrast agent.The decision to use an aspiration catheter (Thrombuster II manual thrombus aspiration catheter, Kaneka Inc., Osaka, Japan) during the primary PCI was determined by the treating physician and was prospectively documented.Per institutional guidelines, an intracoronary glycoprotein IIb/IIIa inhibitor was administered if a TIMI flow score of 3 was not achieved after epicardial revascularization of the culprit artery during the initial presentation with STEMI.Relative contraindications included age > 80 years, a low hemoglobin, history of hemorrhagic stroke or bleeding requiring blood transfusion; the decision to administer glycoprotein IIb/IIIa inhibitor was ultimately determined by the treating physician and prospectively documented.

Coronary physiology assessment
All coronary physiology measurements were performed 3 months after the STEMI by an experienced interventionalist who was blinded to the revascularization technique employed during primary PCI.CFR, fractional flow reserve (FFR), and IMR were assessed using the CoroFlow system (Coroventis Research AB, Uppsala, Sweden).After undergoing successful staged PCI, nitroglycerin was administered through the guiding catheter,

Definitions
STEMI was defined according to the fourth universal definition of myocardial infarction 15 .Door-to-wire time was defined as the time (in minutes) from the first medical contact at the facility to the time of advancement of the PCI wire.Dyslipidemia was defined as a fasting total cholesterol level > 70 mg/dl (1.8 mmol/l) or the use of lipid-lowering medications 16 .Hypertension was defined as a blood pressure ≥ 140/90 mmHg or the use of blood pressure-lowering medication 17 .Diabetes mellitus was defined as a fasting plasma glucose level ≥ 7.0 mmol/l, or the use of blood glucose-lowering medication 18 .MACE was defined as the composite endpoint of cardiovascular death, non-fatal myocardial infarction, target vessel revascularization, recurrent hospitalization due to decompensated heart failure, and stroke (ischemic or hemorrhagic).Renal function was assessed by calculating the glomerular filtration rate using the Cockcroft-Gault equation.
Successful PCI was defined as the implantation of a second-generation drug-eluting stent to the target lesions, resulting in visual reduction of the lesion to less than 20% stenosis, and restoration of coronary blood flow equivalent to both TIMI 2 and TIMI 3 Flow levels.Normal values for FFR, CFR, and IMR were defined as > 0.80, ≥ 2.0, and < 25 U, respectively 19,20 .Microcirculatory dysfunction was defined as IMR ≥ 25 or a CFR < 2.0 7,[19][20][21] .While an IMR > 40 immediately after PCI in STEMI patients has been shown to predict MACE, coronary physiology measurements in this study were performed 3 months after PCI, hence this threshold was not applicable 22 .Nevertheless, a sensitivity analysis examining the incidence of MACE at 12 month follow-up in patients with an IMR < 25, 25 ≤ IMR ≤ 40, and IMR > 40 was performed (Supplemental Fig. 1).

Statistical analysis
Continuous variables were determined to be skewed and therefore were presented as median values with quartile ranges.Categorical variables were presented as frequency and percentage.Wilcoxon Rank Sum, Chi-Square, or Fisher's Exact tests were used to assess baseline differences and outcomes between the study groups, as appropriate.Stepwise selection was used to create multivariable logistic regression models to investigate procedural factors associated with CMD.Kaplan-Meier analysis was used to assess MACE-free survival rates, and differences were evaluated using the log-rank test.A probability level of p < α (where α is the significance level set at 0.05) was assumed to determine statistical significance.Data processing was performed using IBM SPSS Statistics 27.

Ethics approval and consent to participate
We conducted this study in compliance with the ethical standards of the Regional Bioethics Committee of Kaunas, Lithuania (the permission number is BE-2-5) and the World Medical Association Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects.Clinical Trials registration number: NCT05406297, concurrently registered.All subjects gave their informed consent to participate, and an information letter was given to them.

Study population characteristics
This study enrolled 210 patients, of whom 98 patients (46.7%) underwent direct stenting and 112 (53.2%) underwent balloon pre-dilatation before stenting.The median age of the patients was 65 years, falling within an interquartile range of 58 to 76 years.Of the total, 125 patients, accounting for 59.5%, were male.This gender distribution was similar among those who underwent direct stenting and those who received balloon predilatation prior to stenting.Both groups had similar body mass indices, body surface areas, and culprit vessels.Fifty-one (24.3%) patients had diabetes, and 109 (51.9%) patients were current or former smokers, with similar distributions between the two groups.Other risk factors, including arterial hypertension, dyslipidemia, Killip www.nature.com/scientificreports/classification, CHADS2-VASc score, and history of heavy alcohol use, stroke, or coronary artery disease, were also similar between the two groups (Table 1).

Laboratory and echocardiographic findings
Complete blood counts, creatinine clearance, initial troponin and peak troponin levels were similar between the two groups.The direct stenting group had a slightly higher total cholesterol (5.1 mmol/l vs 4.4 mmol/l; p = 0.035) and low-density lipoprotein cholesterol (3.5 mmol/l vs 3.2 mmol/l; p = 0.047).The creatinine clearance rate (40.5 ml/min vs 38.2 ml/min; p = 0.121) and initial troponin levels were similar between the two study groups.

Procedural characteristics and coronary physiology findings
Pain-to-door time (278.5 min vs. 348 min; p = 0.166) and door-to-balloon time (39.0 min vs. 41.5 min; p = 0.318) TIMI flow before and after PCI were similar between the two groups.Furthermore, there were no significant differences in the study groups regarding contrast dose, stent diameter and length, or maximal inflation pressure (Table 3).Three months post-primary PCI, the FFR values exhibited no significant difference between patients who underwent direct stenting and those who were subject to balloon pre-dilatation before stenting (0.92 vs 0.92; p = 0.452).Conversely, CFR values demonstrated a significant increase (2.87 vs 2.70; p < 0.001), and the IMR values displayed a notable decrease (19.5 vs 22.0; p = 0.001) in the patients who underwent direct stenting compared to those who underwent balloon pre-dilatation.Furthermore, there was a lower prevalence of CMD in the direct stenting group (12.2% vs 40.2%; p < 0.001) (Table 3, Fig. 1).

Major adverse cardiovascular events at 12 months
At 12 month follow-up, the incidence of MACE in patients who underwent direct stenting was lower than in those who underwent balloon pre-dilatation before stenting (14.3% vs. 26.8%;p = 0.040) (Table 4, Fig. 2).This difference was driven largely by a decreased incidence of stroke in patients who underwent direct stenting (0% vs 6.3%; p = 0.033).The Kaplan-Meier curve revealed an increased incidence of MACE in patients who underwent balloon pre-dilatation stenting (log-rank p = 0.048), most noticeably starting at 6 months post-PCI (Fig. 3).

Discussion
This prospective, single-blinded, cohort study is one of the largest studies examining the relationship between PCI technique and CMD in STEMI patients.Direct stenting was associated with a lower prevalence of CMD and adverse cardiac events when compared to balloon pre-dilatation before stenting.Both aspiration thrombectomy    and administration of glycoprotein IIb/IIIa inhibitors were associated with lower prevalence of CMD.Unlike prior studies that assessed CMD during the acute phase of STEMI, we performed coronary physiology testing three months after STEMI 23,24 because of altered coronary physiology during the acute phase of STEMI [25][26][27] .Ríos-Navarro et al., in their experimental study, demonstrated a near-complete resolution of CMD 30 days postreperfusion 26 .This hypothesis found further empirical validation in the research conducted by Demirkiran et al., wherein a marked optimization of CMD indices was observed within the 30-day post-STEMI period.Specifically, data demonstrated a decrement in IMR metrics from a pre-established 38.8 to a subsequent 25.6, concomitant with an augmentation in CFR from an initial measurement of 2.16 to a later 3.77 27 .Current guidelines establish primary PCI as the gold standard for treating STEMI patients, but do not specify whether to pursue direct stenting or balloon predilatation 1 .In this study, multivariable logistic analysis showed that direct stenting was associated with approximately fivefold lower odds of CMD compared with balloon pre-dilatation stenting (Table 5, Fig. 5).There are several potential explanations for this observation.First, balloon manipulation within the culprit lesion may cause distal embolization of fragmented thrombus or atheromatous debris, aggravating microvascular occlusion and leading to prolonged myocardial ischemia 28 .Webb and colleagues observed that in saphenous venous graft lesions, direct stenting resulted in less distal embolization than predilatation followed by stenting, likely because thrombus and friable material were entrapped behind the stent struts 29 .Kalayci and colleagues similarly found that STEMI patients treated with direct stenting were less likely to exhibit visible distal embolization (4.4% vs 7.4%; p = 0.014) and were more likely to have complete resolution of ST segment elevation (68.9% vs 59.6%; p < 0.001) than those treated with balloon pre-dilatation stenting 30 .Second, inflation of the balloon within the culprit lesion may release atherogenic plaque components which further activate the coagulation cascade 31 .Third, predilatation may result in arterial wall endothelial dissection and subsequent rapid thrombosis.Fourth,  www.nature.com/scientificreports/pre-dilatation may propagate endothelial damage, triggering an inflammatory response and limiting the appropriate endothelialization of the stented vessel, thereby increasing the risk of stent or neointimal hyperplasia 31 .Direct stenting also has the potential to reduce radiation exposure and healthcare expenditures by reducing procedure time 32 .However, direct stenting also has limitations, including difficulty estimating the caliber of the coronary artery, which may result in inadequate stent expansion, difficulty or failure to deliver or optimally position the stent due to inadequate visualization of the lesion margins 33 .
Previous studies investigating the relationship between PCI techniques and CMD have shown contradictory results.He and colleagues investigated the impact of stenting technique on CMD and did not find that direct stenting had any advantages over balloon predilatation.However, the authors utilized cardiac magnetic resonance (CMR) rather than invasive coronary physiology to assess CMD.Further, they performed CMR 1 week after STEMI, which may be too early to obtain a reliable assessment of coronary microcirculation 26,34 .Kim and colleagues failed to demonstrate any impact of PCI technique on microcirculation.While this study was randomized, it only included 38 patients in each arm, coronary physiology was ascertained immediately after primary PCI, and only IMR was used to assess CMD, rather than both IMR and CFR 23 .Several other randomized controlled trials investigating direct stenting and its effect on myocardial perfusion have been conducted, but are outdated (conducted between the late 1990s and early 2000s) and do not reflect current clinical practice or modern techniques to assess CMD [35][36][37][38][39] .
A study by Scarparo and colleagues found that among STEMI patients who had a higher thrombus burden (TIMI grade flow 0-1), those who were treated with direct stenting had a lower incidence of all-cause mortality at 15 years (hazard ratio (HR) 0.65, 95% CI 0.50-0.84,p = 0.001) and MACE at 10 years (HR 0.71, 95% CI 0.55-0.92,p = 0.010), when compared with those who were treated with balloon pre-dilatation before stenting 40 .
McCormick and colleagues found that balloon pre-dilatation stenting was independently associated with one year mortality OR 2.42, 95 CI 1.08-5.45,p = 0.032) compared with direct stenting.Neither study was randomized 41 .A randomized study by Cuisset and colleagues found a lower IMR with direct stenting compared with balloon pre-dilatation before stenting (13 ± 3 vs.24 ± 14; p < 0.01); however, this study was small (50 patients) and only included patients with stable angina 42 .
The present study also revealed that aspiration thrombectomy during primary PCI was associated with an approximately fivefold decrease in the prevalence of CMD (Table 5, Fig. 5).The use of an aspiration thrombectomy catheter during primary PCI is still being debated in the medical community, with investigations yielding contradictory data 24,[43][44][45] .According to the Thrombectomy Trialists Collaboration study, direct stenting with aspiration thrombectomy during primary PCI did not enhance clinical outcomes or myocardial reperfusion parameters 43 .This is appropriately reflected in the current guidelines, which state that routine use of aspiration thrombectomy is not encouraged 1 .However, the Thrombectomy Trialists Collaboration study used myocardial blush to assess for CMD, rather than invasive thermodilution, CMR, or another quantifiable physiologic index.Hoole and colleagues conducted a randomized clinical pilot trial in which they performed a series of IMR measurements during different stages of primary PCI, followed by CMR analysis at 24 h and three-month follow-up.They found a trend toward less microcirculatory damage in patients who underwent aspiration thrombectomy; however, this did not reach statistical significance.The authors did acknowledge that the results should be interpreted with caution as only 26 patients were included in the CMR analysis, resulting in an underpowered study.Furthermore, IMR was only obtained during primary PCI, which may not be reliable because of altered coronary physiology during STEMI 24 .
The MUltidevice Thrombectomy in Acute ST-Segment Elevation Acute Myocardial Infarction trial, which was the largest randomized trial to evaluate the impact of aspiration thrombectomy on CMD, included 208 STEMI patients and assessed CMD via CMR at 3 months.The aspiration thrombectomy group had a lower prevalence https://doi.org/10.1038/s41598-023-47343-x www.nature.com/scientificreports/A sensitivity analysis examining the incidence of MACE at 12 months according to IMR category revealed a lower incidence of MACE in patients with an IMR < 25, when compared to those with an 25 ≤ IMR ≤ 40 (p < 0.001) and those with an IMR > 40 (p < 0.001).These was no difference in the incidence of MACE at 12 months in patients with an 25 ≤ IMR ≤ 40 and those with an IMR > 40 (p = 0.352) (Supplemental Fig.1).

Figure 1 .
Figure 1.Prevalence of coronary microvascular dysfunction displayed by percutaneous coronary intervention technique.

Figure 2 .
Figure 2. Rates of major adverse cardiac events displayed by percutaneous coronary intervention technique.

Figure 3 .
Figure 3. Kaplan-Meier event-free survival curve for occurrence of major adverse cardiac events grouped by percutaneous coronary intervention technique.

Figure 4 .
Figure 4. Receiver Operating Characteristic curve for the model of coronary microvascular dysfunction in ST-elevation myocardial infarction patients.AUC area under the receiver operating characteristic curve.

Figure 5 .
Figure 5. Forest plot for the outcome of coronary microvascular dysfunction.

Table 1 .
Characteristics of ST-elevation myocardial infarction patients classified by percutaneous coronary intervention technique.STEMI ST elevation myocardial infarction, PCI percutaneous coronary intervention.

Table 2 .
Laboratory and echocardiographic parameters of patients with ST-elevation myocardial infarction, categorized by percutaneous coronary intervention technique.CMD coronary microvascular dysfunction, PCI percutaneous coronary intervention.

Table 4 .
Twelve-month clinical outcomes of patients presenting with ST-elevation myocardial infarction, categorized by percutaneous coronary intervention technique.MI myocardial infarction, HF heart failure, MACE the composite of stroke, nonfatal myocardial infarction, revascularization, heart failure hospitalization, and cardiovascular death.

Table 5 .
Multivariable binary logistic analysis for prediction of coronary microvascular dysfunction after ST-segment elevation myocardial infarction event.